Asthma is an inflammatory disease that is characterized by bronchial hyperresponsiveness, which can lead to life-threatening airway obstructions and be the cause of symptoms such as wheezing, feeling difficulty in breathing (particularly when air is being exhaled) and feeling tight in the chest. Triggers of an asthmatic attack include rapid changes in temperature or humidity, allergies, upper respiratory infections, drastic exercises, stresses and heavy smoking.
Among the above triggers, inhaled allergens resulting in an immune response are understood as one of the most usual factors. In an asthmatic, inhaled allergens that came to the inner airway are ingested by a type of cell known as an antigen presenting cell. An antigen presenting cell then presents pieces of the allergens to another immune cell, for example, a T helper cell, which is a kind of white blood cell helping a human body fight off certain infections. In a healthy person, such an immune cell checks but usually ignores the allergen molecules. In an asthmatic, however, these cells are transformed into a different type of cell such as T helper 2 (Th2). The resultant Th2 cell activates an important arm of the immune system (e.g., the humoral immune system). The humoral immune system produces antibodies against the inhaled allergens. Later, when the asthmatic inhales the same allergens, these antibodies recognize it and activate a humoral response. As a result, chemicals are produced that cause the airway to constrict and release more mucus, and the cell-mediated arm of the immune system is activated.
During an asthmatic episode, an inflamed airway reacts to environmental triggers such as smoke, dust, or pollen. The airway becomes narrow and produces excessive mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airway.
To be more specific, Th2-type cytokine interleukins-4 (IL-4), IL-5 and IL-13 generated by activated CD4+ T cells play a central role in asthmatic pathogenesis, by controlling the key process of immunoglobulin E (IgE) production, growth of mast cells, and differentiation and activation of both mast cells and eosinophils, wherein CD4+ T cells helping B cells make antibodies in response to challenge. Genetic and environmental factors influence the development of Th1 or Th2 cells. The direction of the differentiation of Th cells is determined by the cytokine environment at the site of initial antigenic activation. It has been well known that the presence of IL-4 during the induction phase leads to the predominance of Th2 cells, which subsequently determine the allergic inflammatory responses as described above. Th2 cells are the predominant lymphocyte population that infiltrates the airway of an asthmatic. Moreover, the cytokine products of Th2 cells perform essential roles in airway eosinophilia, airway hyperresponsiveness, and serum IgE production.
Eosinophils are generated in the bone marrow, and recent observations on both mice and humans indicate that pulmonary allergen exposure results not only in an increased output of eosinophils from hemopoietic tissues but also in an increased migration of Th2 cells to the lung. It is the accumulation of activated eosinophils during the late phase response to the allergen exposure that ultimately induces progressive inflammatory tissue damage. Thus, inhibiting Th2 cytokines via the augmentation of Th1 cytokine production may prove useful for treatment of allergic asthma.
In the meantime, suppressor of cytokine signalling (SOCS) is a molecule that functions as a negative regulator of cytokine signaling. SOCS is known to be involved in the pathogenesis of a host (e.g., an animal or a human) that suffers from inflammatory diseases. The discovery of SOCS proteins has provided novel insights into the cytokine regulation of Th1 and Th2 immune responses. Eight members of the SOCS protein family have been identified as follows: cytokine-inducible src homology 2 (SH2) domain-containing proteins and SOCS-1 to SOCS-7.
Among the SOCS proteins, SOCS-3 is expressed preferentially in Th2 cells and plays a crucial role in regulation of the onset and maintenance of Th2-mediated allergic diseases. The concentration of serum IgE is also increased in an asthmatic, and this can be interpreted as an evidence of high SOCS-3 expression. On the other hand, SOCS-5 is expressed preferentially in Th1 cells, and its expression can result in reduction of Th2 differentiation due to the inhibition of IL-4 signaling.
Therefore, the inhibition of SOCS-3 expression may be a useful therapeutic approach to the treatment of Th2-dominant diseases, including allergic asthma.